What is the mechanism of action (MoA) of inhaled nitrous oxide (N2O)?

From the Guidelines

Nitrous oxide works primarily by inhibiting N-methyl-D-aspartate (NMDA) receptors in the brain, resulting in analgesia and sedation, and its mechanism of action also involves stimulating the release of endogenous opioids and affecting GABA receptors, contributing to its anxiolytic effects. When inhaled, nitrous oxide rapidly diffuses across the alveolar membrane into the bloodstream and then crosses the blood-brain barrier 1. Its pharmacokinetic profile, which includes rapid onset (30-60 seconds) and offset (3-5 minutes) of action, makes it useful for short procedures requiring mild to moderate analgesia and anxiolysis, particularly in dental procedures and emergency settings.

Key Points

• Nitrous oxide is an inhalational agent coadministered with oxygen, with benefits including rapid onset, rapid recovery, and an excellent safety profile 1.
• The gas is minimally metabolized in the body (less than 0.004%) and is primarily eliminated unchanged through the lungs, allowing for rapid onset and offset of action.
• Nitrous oxide has minimal effects on cardiovascular function and does not significantly depress respiratory drive at clinical concentrations.
• Some potential side effects of nitrous oxide include headache, hypertension, arrhythmias, nausea, vomiting, and hypoxia, which can be avoided by coadministration with 30% to 50% oxygen 1.

Clinical Use

• Nitrous oxide may have potential value for endoscopic sedation, with some studies showing that patients receiving this agent have better overall satisfaction and assessment of pain, and shorter time to discharge compared to those receiving intravenous sedation 1.
• However, some patients receiving nitrous oxide may require intravenous sedation to complete their examination, and headache has been a troubling side effect of nitrous oxide in several studies 1.

From the Research

Mechanism of Action of Inhaled Nitrous Oxide

• Inhaled nitrous oxide acts as a non-competitive inhibitor of NMDA-type glutamate receptors 2
• The mechanisms of action of nitrous oxide are not fully understood, but it is known to have analgesic, anxiolytic, and anesthetic effects 3
• The analgesic effect of nitrous oxide is opioid in nature, and may involve a myriad of neuromodulators in the spinal cord 3
• The anxiolytic effect of nitrous oxide resembles that of benzodiazepines and may be initiated at selected subunits of the gamma-aminobutyric acid type A (GABA(A)) receptor 3
• The anesthetic effect of nitrous oxide may involve actions at GABA(A) receptors and possibly at N-methyl-D-aspartate receptors as well 3

NMDA Receptor Antagonism

• Nitrous oxide has been shown to have NMDA receptor channel blocker-like discriminative stimulus effects 4
• The high-affinity NMDA receptor channel blocker (+)-MK-801 maleate and the low-affinity blocker memantine partially mimicked the stimulus effects of nitrous oxide 4
• Chronic exposure to nitrous oxide increases [3H]MK801 binding in the cerebral cortex, but not in the hippocampus of adult mice, indicating an upregulation of NMDA receptors 5
• Nitrous oxide pre- and postsynaptically attenuates NMDA receptor-mediated neurotransmission in the amygdala 6

Clinical Implications

• Inhaled nitrous oxide is used for inhalational general anesthesia and analgesia for short procedures 2
• Nitrous oxide has been shown to reduce depressive symptoms in a group of severely ill treatment-resistant depression patients 2
• The use of nitrous oxide as a rapid-acting antidepressant agent is currently being studied, but further investigation is needed 2